Hematologic Disease in Pregnancy &

Hemoglobinopathies

Darren Farley, MDClinical Assistant Professor

Division of Maternal-Fetal MedicineDept. of Obstetrics and Gynecology

University of Kansas School of Medicine – Wichita

• No financial interests to disclose.

Physiologic changes in pregnancy

• Anemia in pregnancy• First/third trimester – Hb <11g/dL• Second trim – Hb <10.5g/dL

• Iron requirements in pregnancy– Total 1000mg

• 300mg (fetus/placenta)• 500mg (expansion of maternal Hb mass)• 200mg (shed through gut, urine, skin)

Pregnancy associated changes in coagulation

• Increased concentration of all clotting factors except for XI, XIII and Protein S free levels which decrease– Fibrinogen, II, V, VII, VIII, IX, X, XII, PAI-1, 2

• 200% increase– Von Willebrand factor increases 100-150%

• Decrease – XI, XIII, protein S• Unchanged - Protein C, Antithrombin (ATIII)• Levels of thrombin-ATIII complex increase, suggesting

coagulation activation is consistent with elevated fibrinopeptides

Coagulation changes• Fibrinogen level (increased concentration with increased

plasma volume)– Avg nonpregnancy 300mg/dL (200-400)– Avg pregnancy increase is 50%; 450mg/dL late in

pregnancy (300-600)• End product of coagulation cascade is fibrin

formation• Prothrombin time – no change• Partial thromboplastin time – no change

ACOG 2007

• IV iron– Iron Dextran

(0.6-1% rate of anaphylaxis)

– Iron sucrose (lower rate of anaphylaxis and fatality rates)

– Ferric gluconate

Autologous transfusion – Hct >32% at 32 weeks

Severe anemia

• Severe anemia with maternal Hb <6g/dL has been asssociated with abnormal fetal oxygenation resulting in NR FHR patterns, oligohydramnios, fetal cerebral vasodilatatoin and fetal death. Thus maternal transfusion should be considered for fetal indications.

ACOG

Hemoglobinopathies• Definition –

– qualitative (sickle cell – Beta globin gene mutation)

– quantitative (thalassemia, unbalance of alpha or beta globin chains) abnormality in the hemoglobin molecule

• Incidence – allele frequency depends on ethnicity; – worldwide > 270 million heterozygous carriers; – > 300,000 affected homozygotes or compound

heterozygotes born each year (ACOG 2007)

Sickle cell anemia – Overview • Definition – AR hemoglobin disease due βglobin chain (chromosome 11)

missense mutation that substitutes valine for glutamic acid at amino acid 6 (β-globin glu6val mutation)

• Incidence – 1 in 700 (African), carrier rate -~1 in 10• Pathogenesis – the glu6val mutation DECREASES the solubility and

deformability of the βglobin chain so that after repeated cycles oxygenation and attendant sickling, the chains become permanently ‘sickled’ and occlude capillaries causing infarctions (painful crisis, acute chest syndrome, asplenia); irreversible sickled cells are removed by the spleen and the rate of removal of erythrocytes from the circulation exceeds the production capacity of the bone marrow and causes a hemolytic anemia

• Diagnosis – Peripheral smear; Hemoglobin electrophoresis identifying Hb SS (p100 Gehleter) – normal adult A (97.5%), A2 (2%), F (0.5%)

(uptodate)

Peripheral smear from a patient with sickle cell anemia shows multiple spindly sickle cells (blue arrows), a nucleated red blood cell in the upper left, and a Howell-Jolly body (black arrow), which is a nuclear fragment normally removed by the spleen. Target cells are also present (red arrow). This patient has functional asplenia because of repeated splenic infarctions. Courtesy of Carola von Kapff, SH (ASCP).

Hgb electrophoresisElectric fieldSickle (glu6val) valine in place of glutamineGlutamine has a moreNegative charge thus it travels further than Valine (S) or lysine (C)-A = glutamine has the most negative charge –thus it goes far on the gel-S = glutamine to valine (middle charge b/n +/-)-C = glutamine to lysine (more + charge thus it does not goes as far on the gel)-A2 (most positive charge, thus it does not go far on the gel)

Hb C/A2

Gelehrter p 100

Sickle Cell Disease and genetic principles

• Heterozygote advantage, plays role in ethnic variation in allele frequency

• Novel property mutation - sickle cell disease is an exception to the allelic heterogeneity rule in that one specific mutation is responsible for the unique ‘novel’ properties of sickle Hb; Hb C is less soluble than Hb A and tends to crystallize in red cells, decreasing the deformability in capillaries and this also creates mild hemolysis, but Hb C does not sickle or form the rod shaped polymers like Hb S

• Ethnic variation in allele frequency

Sickle cell allele/mutation frequencies (Nussbaum 4th ed) –California cohort dataEthnicity HB SS Hb ASAfrican American 1/700 1/14Asian Indian 0/1600 1/700Hispanic 1/46,000 1/180Middle Eastern 0/22,000 1/360Native American 1/17,000 1/180White 1/160,000 1/600Asian 0/200,000 1/1300

Hardy-Weinberg Principle & Assumptions

• 2 components • 1 – Under certain ideal conditions a simple relationship exists between

allele frequencies and genotype frequencies in a population– The HW Law states that the frequency of the three genotypes AA, Aa,

and aa is given by the terms of the binomial expansion of (p+q)² = p² + 2pq + q²

• 2- – If allele frequencies do not change from generation to generation, the relative proportion of the genotypes will not change either; that is the population genotype frequencies from generation to generation will remain constant, at equilibrium, if the allele frequencies p and q remain constant. More specifically, when there is random mating in a population that is at equilibrium and genotypes AA, Aa, and aa are present in the proportions p² :2pq:q² , then genotype frequencies in the next generation will remain in the same relative proportions, p² :2pq:q²

(T/T Genetics in Medicine)

HW Assumptions

• The population is large and matings are random with respect to the locus in question

• Allele frequencies remain constant over time because:– There is no appreciable rate of mutation– Individuals with all genotypes are equally capable of

mating and passing on their genes, that is, there is no selection against any particular genotype

– There has been no significant immigration of individuals from a population with allele frequencies very different from the endogenous population

(T/T Genetics in Medicine)

Hardy-Weinberg example• Williams quest – What is approximate

incidence of sickle cell anemia in African Americans if carrier rate is 1/12?

• 1=p+q• 1=p2 + 2pq + q2

• p = dominant allele• q = recessive allele

• 1/12 x 1/12 x ¼ = 1 in 576

HW – PKU example• PKU• Frequency of affected homozygotes in the population can be determined accurately

through newborn screening programs• Heterozygotes – asymptomatic silent carriers, population incidence is impossible to

measure directly from phenotype• HW law allows estimate of heterozygote frequency to be made and used subsequently

for counseling• Frequency of PKU 1 in 4500 – 1/4500 in Ireland

– Frequency of affected individuals = 1/4500 = q², q =0.015, and 2pq = 0.029 or approx ~3%

• Carrier frequency in the Irish population ~3% • If pt is a known carrier – Partner is Irish (3% heterozygote rate)

– Chance of affected offspring – 0.5 x 0.03 x 0.25 = 1 in 267– Chance of carrier offspring - 0.5 x 0.03 x 0.5 = 1 in 133

• If pt is known carrier – Partner is from Finland (PKU frequency 1/200,000)– Frequency of affected individuals = 1/200,000 = q², q =0.002, and 2pq = 0.004 =

0.4% = carrier rate– Chance of affected offspring = 0.5 x.004 x .25 = 1 in 2000 – Chance of carrier offspring = 0.5 x 0.004 x 0.5 = 1 in 1000

(T/T Genetics in Medicine)

Sickle Cell Disease & Pregnancy• Increased risk of morbidity/mortality – depends on severity of anemia

– Hb SS and to lesser extent Hb SC- Risks include infection, acute chest syndrome, pain crises, dehydration, severe anemia, cholecystitis, preterm birth, low-birth weight infants (<2500g), fetal growth restriction, hospitalization, IUFD

– Folic acid supplementation – 4mg/day– Painful crisis (tx with pain control, oxygen, IV hydration) – avoid cold

temp, heavy exertion, dehydration, stress– Acute chest syndrome (fever, tachypnea, chest pain, hypoxia)– Autosomal recessive implications for offspring– Prophylactic or exchange transfusion – goal of Hct - >21% (ideal ~30%) –

decreases risk of painful crises, severe anemia, not necessarily associated with improved pregnancy outcome, less crises, less anemia (ACOG 2007)

– Vaccinations – Pneumococcal vaccine and Meningococcal and Haemophilus influenza type B

– Serial Urine cultures -

Pregnancy and Sickle Cell Disease-Risks

• Maternal death – Mortality 72 deaths per 100,000 deliveries versus 12.7 deaths per 100,000 deliveries in women without SCD.

• Transfusion (OR 22.5; 95% CI 18.7-27.0)• Systemic inflammatory response syndrome (SIRS; OR 12.6; 95% CI 2.1-13.6)• Pneumonia (OR 9.8; 95% CI 8.0-12.0)• Sepsis (OR 6.8; 95% CI 4.4-10.5)• Asymptomatic bacteriuria (OR 6.8, 95% CI 3.1-14.9)• Cerebral vein thrombosis (OR 4.9; 95% CI 2.2-10.9)• Deep vein thrombosis (OR 2.5; 95% CI 1.5-4.1)• Genitourinary tract infection (OR 2.3, 95% CI 1.9-2.7)• No difference in stroke, PE, MI, pyelonephritis

The largest data set of SCD outcomes in pregnant women is the Nationwide Inpatient Sample from the Healthcare Cost and Utilization Project of the US Agency for Healthcare Research and Quality, which analyzed all pregnancy-related discharges with a diagnosis of SCD for the years 2000 to 2003, and included almost 18,000 deliveries to women with SCD and 17 million deliveries to women without the disease - Villers 2008

Pregnancy and Sickle Cell Disease-Risks

• Villers – 2008 - N = 286 SCD pregnancies• Risks increased of • Intrauterine growth restriction (OR 2.2; 95% CI 1.8-2.6)• Eclampsia (OR 3.2; 95% CI 1.8-6.0)• Gestational hypertension and preeclampsia (OR 1.2; 95% CI 1.1-1.3)• Preterm labor (OR 1.4; 95% CI 1.3-1.6)• Postpartum infection (OR 1.4; 95% CI 1.1-1.7)• Abruption (OR 1.6; 95% CI 1.2-2.1)• Antepartum bleeding (OR 1.7; 95% CI 1.2-2.2)• Lower rate of PPH • No difference in GDM rates. Inadequate number to assess risk of IUFD.

Villers 2008

Complications

• Secondary organ system effects– >80% of sickle cell patients have

cardiomegaly (baseline echocardiogram, EF)– Prolongation of PR interval

• Crisis – Hematologic – Pediatric pop, rare in

pregnancy– Vaso-occlusive -

Evaluation• Diagnosis• Echocardiogram• PFTs• Partner Carrier screening• Hep B, C testing• Retinal evaluation (retinopathy can

worsen)• Serial urine cultures

Sickle crisis• Hematologic

– Aplastic crisis – usually due to infection (bacterial, viral), human parvo (also risk to fetus)

• Risk of stroke with severe anemia• Transfusion if HCT <25%

• Vaso-occlusive – Splenic sequestration – Hepatic sequestration– Hyperhemolytic sequestration

Sickle crisis - Pain

• Acute pain crisis• 1/3 are associated with infection• Management – Rest, hydration,

oxygenation, pain control, antibiotics if infection is suspected

Algorithm –CCO

Critical Care OB - Dildy

Algorithm –CCO

Critical Care OB - Dildy

Sickle crisis – Pulmonary crisis

• Acute chest syndrome – potentially fatal• Fever, pleuritic cp, tachypnea,

pulmonary infiltrates• DDX – PE, fat embolism, AFE• Tx – oxygenation, hydration, treatment

of infection, pain control• Transfusion to increase HbA >40%, Hct

<30%, HBS<60%

ACS• Diagnostic criteria for ACS — ACS is defined as radiographic evidence of consolidation: a new

segmental (involving at least one complete segment) radiographic pulmonary infiltrate [3], AND at least one of the following:

• Temperature ≥38.5°C• >2 percent decrease in SpO2 (O2 saturation) from a documented steady-state value on room air

(FiO2 = 0.21)• PaO2 <60 mmHg• Tachypnea (per age-adjusted normal)• Intercostal retractions, nasal flaring, or use of accessory muscles of respiration• Chest pain• Cough• Wheezing • Râles• Of importance, the presence of pneumonia can formally be considered as meeting the criteria

for ACS, since the two cannot be reliably distinguished from one another.

uptodate

ACS severity index — Severity of ACS is considered mild, moderate, severe, or very

severe,• Mild ACS — Meets the diagnostic criteria for ACS plus ALL of the following:• Transcutaneous oxygen saturation >90 percent on room air (FiO2 = 0.21)• Segmental or lobar infiltrates that involve no more than one lobe by chest radiography• Responsive to simple transfusion of no more than 2 units of red blood cells (or 15 mL/kg of

packed RBCs)

• Moderate ACS — Meets the diagnostic criteria for ACS plus ALL of the following:• Transcutaneous oxygen saturation ≥85 percent on room air (FiO2 = 0.21)• Segmental or lobar infiltrates that involve no more than two lobes by chest radiography• Responsive to transfusion of ≥3 units of red cells (or >20 mL/kg packed RBCs)

uptodate

• Severe ACS — Meets the diagnostic criteria for ACS plus one or more of the following:

• Respiratory failure present (PaO2 <60 mmHg or PCO2 >50 mmHg)• Mechanical ventilatory support required• Transcutaneous oxygen saturation <85 percent on room air or ≤90 percent despite

maximal supplemental O2

• Segmental or lobar infiltrates that involve three or more lobes by chest radiography

• Requiring transfusion or exchange transfusion of RBCs to achieve hemoglobin A levels ≥70 percent

• Very severe ACS — Acute respiratory distress syndrome (ARDS) present or sudden, life-threatening lung failure. ARDS is defined by the following three criteria of the American-European Consensus Conference and includes:

• Acute onset of bilateral infiltrates on chest radiography• Pulmonary artery wedge pressure <19 mmHg or the absence of clinical evidence of

left atrial hypertension• PaO2/FiO2 ≤200 regardless of positive end expiratory pressure (PEEP) level

ACS severity index — Severity of ACS is considered mild, moderate, severe, or very severe,

uptodate

Hepatic crisis

• Vaso-occlusion of hepatic vasculature• Fever, RUQ pain, leukocytosis, elevated

LFTs, bilirubin• DDX – choleycystitis, HELLP sd• Management – hydration, pain control,

antibiotics, serial labs

Exchange transfusion• Prophylactic partial exchange transfusions prior to

onset of vaso-occlusive crisis• Decreased incidence of pain crisis, less maternal

anemia, no consistent improvement in perinatal outcome

• Transfusion to increase HbA >40%, Hct <30%, HBS<60%– Standard exchange of 6 units of washed packed RBCs,

increases HbA to 70%– Tables used to calculate required volume of transfusion given

% of Hb A, Hct of transfused blood, patient weight (kg)

• Alloimmunization is main risk, thus prophylactic transfusions are not recommended

Simple transfusion

• Hb/Hct <6-7g/dL, 18-21%• Goal of HCT <30% so as to avoid

increased viscosity of blood which can precipitate a crisis

Medical therapy

• Hydroxyurea (increases amount of HbF)– Selectively cytotoxic in bone marrow,

increases # of erythroblasts producing HbF– Cytotoxic – risk of teratogenicity and

carcinogenicity– Case reports/series with favorable outcomes,

no long term follow up– Not recommended in pregnancy

Medical therapy

• EPO – erythropoietin – hormone that stimulates red cell production– Possible stimulation of HbF production– Not used for HbF induction in sickle patients– May be used in sickle patients with renal

insufficiency – (A/E HTN)

Medical therapy

• Prophylactic PCN – OK to continue during pregnancy if on PPX prior to pregnancy– Do not need to initiate PPX due to

pregnancy• Deferoxamine - D/c with pregnancy• ACE inhibitors/ARBs – D/c with

pregnancy

Conclusions• Care in Pregnancy• Crisis management• Keep inheritance patterns and

recurrence risk straight• Use OMIM, GeneTest for review and

options for prenatal diagnosis and counseling

Thalassemias

PathogenesisGelehter p 105

Thalassemias –Beta globin gene -- chromosome 11Alpha globin gene --chromosome 16

Life spanOf RBC 120d

Classification of α/β-Thalassemias (ACOG bulletin, Nussbaum, Gelehter)

Number offunctional Globin Genes

(ratio of α/β globin)Genotype Description

ClinicalFeatures

4 (1) αα/αα Normal Normal3 (0.8) α-/αα Heterozygous

α-thal trait (silentcarrier)

Asymptomatic (silent carrier)

2 (0.6) α-/α-αα/--

“α-thal trait” affected Mildanemia

1 (0.3) α-/--1α, rest β

Hb H disease (β4 tetramers detected)

Hb H – marked hemolytic anemia at

birth (MCV<50mm3)

0 (0) --/--All 4 γ

Hb Bart’s – no alpha globin

Hb Bart's (hydropsfetalis)

α thalassemia – diagnosed by DNA based testing (S. blot, PCR, ASO)βthalassemia - βchain deficiency (Hb electrophoresis - >0.5% F, >3.5%% A2)

α-thalassemia• Autosomal recessive; Classification table• Chromosome 16 – 2 functioning α genes

– Heterozygous α thal 2 (α-/αα) – silent carrier– ‘α thal trait’ – α thal 1 (2 of 4 α globin genes deleted)

• Southeast Asians – (αα/--) heterozygous for α 1, 2• Blacks – (α-/α-) – homozygous for α thal 2 chromosome • MCV slightly reduced, asymptomatic

– Hb H α-/-- essentially all 4 Beta chains, severe anemia– Hb Barts – hydrops (--/--) all gamma chains

• Most common abnormality – leads to loss of 1 α-globin gene on a chromosome – unequal crossing over of α-globin cluster on chromosome 16– High degree of homology of nucleotide sequences around α1 and α2

genes

Gelehrter p107-109

β thalassemia• Autosomal recessive; β-globin gene Chromosome 11• Large number of mutations that can result in decreased or

absent function of β-globin gene• Due to 1 β globin gene per chromosome 11, chance for unequal

crossing over is much reduced (vs α thal)• Classes

– Minor – 1 normal β-gene, 1 nonfunctional gene– Intermedia – abnormality of both β-globin chains, anemic,

symptomatic, but not transfusion dependent– Major – No β-globin made (both genes mutated), no Hb A

made, severe anemia, transfusion dependent

Gelehrter p107-109

Thalassemia (α/β) – overview • Definition – quantitative abnormality of the globin chains• Incidence – α-thal trait - 0.01% in nonmalarial exposed populations

Iceland, UK, Japan; 49% in southwest Pacific islanders– Hb H disease, hydrops fetalis – restricted to Mediterranean and SE

Asia– β-thal trait – 1-2% Africans and African Americans; 30% in Sardinia

• Pathogenesis - deficient synthesis of α-globin or β-globin chain that forms the hemoglobin molecule, unbalanced accumulation of alpha/beta subunits (Gelehrter, p96); childhood onset, hypochromic microcytic anemia, HSM, extramedullary hematopoiesis– ~80% untreated pts die within 5 years; – Transfusion therapy alone – death <30yo (due to infection,

hemochromotosis)– Iron chelation therapy can reduce chance of hemochromotosis and

cardiac, hepatic complications - from repeated transfusions

(OMIM)

Thalassemia – genetic principles

• Heterozygote advantage – carriers of trait display resistance to malaria; prevalence in an ethnic group reflects past and present exposure of a population to malaria– Ethnic variation in allele frequencies

• Gene dosage – amount of gene present affects degree of symptoms

Thalassemia & Pregnancy• Thalassemia trait not increased risk• Autosomal recessive implications, Screening at risk ethnic groups

(Asians, Mediterranean, Blacks)• Thalassemia major (little to no β chain production)- pregnancy is

recommended if normal cardiac function, Hb > 10g/dL after hypertransfusion and iron chelation therapy (ACOG 2007) – During pregnancy Hb goal >10 g/dL ; Deferoxamine stopped – Fetal testing (serial growth scans, weekly testing); CD for

obstetric indications – Echocardiogram prepregnancy

• β -thalassemia minor – mild anemia; only ppx iron; fetal testing (ACOG 2007)

• Supportive therapy – Hct >21% (Hb >6g/dL); ideal Hct > 30%

Conclusions

• Keep inheritance patterns and recurrence risk straight

• Use OMIM, GeneTest for review and options for prenatal diagnosis and counseling

• QUESTIONS ??

Texas Newborn Screeninghttp://www.dshs.state.tx.us/LAB/NBSdisorderList.pdf

• Amino Acid Disorders - Phenylketonuria (PKU), Maple Syrup Urine Disease (MSUD), Homocystinuria (HCY), Tyrosinemia Type I (TYR I), Argininosuccinic acidemia (ASA), Citrullinemia (CIT)

• Fatty Acid Disorders - Medium chain Acyl-CoA dehydrogenase deficiency (MCAD), Very Long chain Acyl-CoA dehydrogenase deficiency (VLCAD), Long Chain Hydroxy Acyl-CoA dehydrogenase deficiency (LCHAD), Trifunctional protein deficiency (TFP), Carnitine uptake defect (CUD),

• Organic Acid Disorders - Isovaleric Acidemia (IVA), Glutaric Aciduria Type I (GA-I), 3-hydroxy-3-methylglutaryl CoA lyase deficiency (HMG), Multiple carboxylase deficiency(MCD), Methylmalonic Acidemia/Methylmalonyl-CoA mutase (MUT), Methylmalonic Acidemia/Vitamin B12 Disorders (Cbl A,B), 3-methylcrotonyl-CoA carboxylase deficiency (3MCC), Propionic Acidemia (PROP), Beta ketothiolase deficiency (BKT),

• Hemoglobinopathies - Sickle Cell Anemia (SCA), Sickle C Disease (HB S/C), Sickle Beta Thalassemia (HB S/Th)

• Other Disorders - Hypothyroidism (HYPOTH), Biotinidase deficiency (BIO), Congenital Adrenal Hyperplasia (CAH), Transferase Deficient Galactosemia (GALT), Cystic Fibrosis (CF), Hearing (HEAR)

Kansas Newborn Screeninghttp://www.kdheks.gov/newborn_screening/disorder_listing.htm

• Amino Acid Disorders - Phenylketonuria (PKU), Maple Syrup Urine Disease (MSUD), Homocystinuria (HCY), Tyrosinemia Type I (TYR I), Argininosuccinic acidemia (ASA), Citrullinemia (CIT)

• Fatty Acid Disorders - Medium chain Acyl-CoA dehydrogenase deficiency (MCAD), Very Long chain Acyl-CoA dehydrogenase deficiency (VLCAD), Long Chain Hydroxy Acyl-CoA dehydrogenase deficiency (LCHAD), Trifunctional protein deficiency (TFP), Carnitine uptake defect (CUD),

• Organic Acid Disorders - Isovaleric Acidemia (IVA), Glutaric Aciduria Type I (GA-I), 3-hydroxy-3-methylglutaryl CoA lyase deficiency (HMG), Multiple carboxylase deficiency(MCD), Methylmalonic Acidemia/Methylmalonyl-CoA mutase (MUT), Methylmalonic Acidemia/Vitamin B12 Disorders (Cbl A,B), 3-methylcrotonyl-CoA carboxylase deficiency (3MCC), Propionic Acidemia (PROP), Beta ketothiolase deficiency (BKT),

• Hemoglobinopathies - Sickle Cell Anemia (SCA), Sickle C Disease (HB S/C), Sickle Beta Thalassemia (HB S/Th)

• Other Disorders - Hypothyroidism (HYPOTH), Biotinidase deficiency (BIO), Congenital Adrenal Hyperplasia (CAH), Transferase Deficient Galactosemia (GALT), Cystic Fibrosis (CF), Hearing (HEAR)

References

• Genetic in Medicine –Thompson/Thompson

• ACOG PB• MFM Principles – Creasy• Critical Care OB - Dildy

Notes

• – G3P2 30 weeks – Fatigue complaints. Hb 8g/dL. Peripheral smear, RBC indices c/w hypochromic microcytic anemia. Next step in management –

• Spherocytosis• 23yo 16wks – c/o fatigue, n/v, yellow eyes.

CBC – severe anemia ; peripheral smear c/s spherocytosis

Notes- Case – 22 yo P2002; SCA; Hx of 2 days of bone pain, typical of

past bone crisis; CBC – Hb 6.5g/dL; Transfusion will increase blood count, but not decrease duration of the acute pain crisis or improve her pain symptoms.

- Complications include stroke

• Case 18yo P0000, hx sickle cell anemia – 19 weeks with fever shortness of breath and chest pain; CXR with pulmonary consolidation; CT with consolidation/infiltrate – what can precipitate this condition?

• What is condition –• PPTs- infection, bone marrow emboli, atelectasis, VTE; vaso

occlusive crisis of sickle cell disease, pulmonary infarcts; VTE

Notes

• 28yo P2002 at 8 weeks – Hx of ITP –Counseling/evaluation/management

• 28yo P0000 at 28 weeks, no known hx of ITP; platelet count –– 105k (DDX, counseling, management), – 65k (DDX, counseling, management), – 15k (DDX, counseling, management

ACS• Diagnostic criteria for ACS — ACS is defined as radiographic evidence of consolidation: a new

segmental (involving at least one complete segment) radiographic pulmonary infiltrate [3], AND at least one of the following:

• Temperature ≥38.5°C• >2 percent decrease in SpO2 (O2 saturation) from a documented steady-state value on room air

(FiO2 = 0.21)• PaO2 <60 mmHg• Tachypnea (per age-adjusted normal)• Intercostal retractions, nasal flaring, or use of accessory muscles of respiration• Chest pain• Cough• Wheezing • Râles• Of importance, the presence of pneumonia can formally be considered as meeting the criteria

for ACS, since the two cannot be reliably distinguished from one another.

ACS severity index — Severity of ACS is considered mild, moderate, severe, or very

severe,• Mild ACS — Meets the diagnostic criteria for ACS plus ALL of the following:• Transcutaneous oxygen saturation >90 percent on room air (FiO2 = 0.21)• Segmental or lobar infiltrates that involve no more than one lobe by chest radiography• Responsive to simple transfusion of no more than 2 units of red blood cells (or 15 mL/kg of

packed RBCs)• Moderate ACS — Meets the diagnostic criteria for ACS plus ALL of the following:• Transcutaneous oxygen saturation ≥85 percent on room air (FiO2 = 0.21)• Segmental or lobar infiltrates that involve no more than two lobes by chest radiography• Responsive to transfusion of ≥3 units of red cells (or >20 mL/kg packed RBCs)

• Severe ACS — Meets the diagnostic criteria for ACS plus one or more of the following:

• Respiratory failure present (PaO2 <60 mmHg or PCO2 >50 mmHg)• Mechanical ventilatory support required• Transcutaneous oxygen saturation <85 percent on room air or ≤90 percent despite

maximal supplemental O2

• Segmental or lobar infiltrates that involve three or more lobes by chest radiography

• Requiring transfusion or exchange transfusion of RBCs to achieve hemoglobin A levels ≥70 percent

• Very severe ACS — Acute respiratory distress syndrome (ARDS) present or sudden, life-threatening lung failure. ARDS is defined by the following three criteria of the American-European Consensus Conference and includes:

• Acute onset of bilateral infiltrates on chest radiography• Pulmonary artery wedge pressure <19 mmHg or the absence of clinical evidence of

left atrial hypertension• PaO2/FiO2 ≤200 regardless of positive end expiratory pressure (PEEP) level

ACS severity index — Severity of ACS is considered mild, moderate, severe, or very

severe,

Uptodate chest sd

Uptodate SCD in preg

Pregnancy and Sickle Cell Disease-Risks

• Maternal death – Mortality 72 deaths per 100,000 deliveries versus 12.7 deaths per 100,000 deliveries in women without SCD.

• Transfusion (OR 22.5; 95% CI 18.7-27.0)• Systemic inflammatory response syndrome (SIRS; OR 12.6; 95% CI 2.1-

13.6)• Pneumonia (OR 9.8; 95% CI 8.0-12.0)• Sepsis (OR 6.8; 95% CI 4.4-10.5)• Asymptomatic bacteriuria (OR 6.8, 95% CI 3.1-14.9)• Cerebral vein thrombosis (OR 4.9; 95% CI 2.2-10.9)• Deep vein thrombosis (OR 2.5; 95% CI 1.5-4.1)• Genitourinary tract infection (OR 2.3, 95% CI 1.9-2.7)

Evaluation

• Diagnosis• Echocardiogram• PFTs• Partner Carrier screening• Hep B, C testing• Retinal evaluation (retinopathy can

worsen)• Serial urine cultures

(uptodate)

Peripheral smear from a patient with sickle cell anemia shows multiple spindly sickle cells (blue arrows), a nucleated red blood cell in the upper left, and a Howell-Jolly body (black arrow), which is a nuclear fragment normally removed by the spleen. Target cells are also present (red arrow). This patient has functional asplenia because of repeated splenic infarctions. Courtesy of Carola von Kapff, SH (ASCP).

Hgb electrophoresisElectric fieldSickle (glu6val) valine in place of glutamineGlutamine has a moreNegative charge thus it travels further than Valine (S) or lysine (C)-A = glutamine has the most negative charge –thus it goes far on the gel-S = glutamine to valine (middle charge b/n +/-)-C = glutamine to lysine (more + charge thus it does not goes as far on the gel)-A2 (most positive charge, thus it does not go far on the gel)

Hb C/A2

Gelehrter p 100

Sickle Cell Disease and genetic principles

• Heterozygote advantage, plays role in ethnic variation in allele frequency

• Novel property mutation - sickle cell disease is an exception to the allelic heterogeneity rule in that one specific mutation is responsible for the unique ‘novel’ properties of sickle Hb; Hb C is less soluble than Hb A and tends to crystallize in red cells, decreasing the deformability in capillaries and this also creates mild hemolysis, but Hb C does not sickle or form the rod shaped polymers like Hb S

Sickle cell mutation frequencies (Nussbaum 4th ed) –California cohort dataEthnicity HB SS Hb ASAfrican American 1/700 1/14Asian Indian 0/1600 1/700Hispanic 1/46,000 1/180Middle Eastern 0/22,000 1/360Native American 1/17,000 1/180White 1/160,000 1/600Asian 0/200,000 1/1300

Sickle cell disease & Pregnancy• Increased risk of morbidity/mortality – depends on severity of anemia

– Hb SS and to lesser extent Hb SC- Risks include infection, acute chest syndrome, pain crises, dehydration, severe anemia, cholecystitis, preterm birth, low-birth weight infants (<2500g), fetal growth restriction, hospitalization

– Folic acid supplementation – 4mg/day– Painful crisis (tx with pain control, oxygen, IV hydration) – avoid cold

temp, heavy exertion, dehydration, stress– Acute chest syndrome (fever, tachypnea, chest pain, hypoxia)– Autosomal recessive implications for offspring– Prophylactic or exchange transfusion – goal of Hct - >21% (ideal ~30%) –

decreases risk of painful crises, severe anemia, not necessarily associated with improved pregnancy outcome, less crises, less anemia (ACOG 2007)

Screening in pregnancy (ACOG, 2007)

• CBC, hemoglobin electrophoresis, ferritin (<10 mcg/dL – iron deficiency)

• Individuals of African, Southeast Asian, and Mediterranean descent are at increased risk for being carriers of hemoglobinopathies and should be screened

• Carriers or affected patients – genetic counseling, prenatal diagnosis if mutations have been defined in the parents for thalassemia – DNA mutation analysis for sickle cell disease is available 2 carriers or affected patients

• MCV < 80fL, normal ferritin – screen with hemoglobin electrophoresis

ACOG 2007

Conclusions

• Keep inheritance patterns and recurrence risk straight

• Use OMIM, GeneTest for review and options for prenatal diagnosis and counseling

Hematology

• END

Renal Disease in Pregnancy

• October 22, 2014

• See ppt slides in folder of renal disease in preg

• Physiology• DM nephropathy• Lupus nephritis• Renal transplant• Indications for Dialysis• Oliguria in severe preeclampsia

Renal Disease in Pregnancy

• END

GI Disease in Preg

• Jan 28 2015

• See notes, ppt• See notes from previous Willams Review

GI Disease in Pregnancy

• END

Endocrinology Emergencies/Disease in

Pregnancy • DIABETES• Mar 25 2015

• See notes, ppt – see ppt on this talk –from Mar 2012

• See notes from previous Willams Review

• END

Endocrinology Emergencies/Disease in

Pregnancy

Endocrinology Emergencies/Disease in

Pregnancy • THYROID• MAY 20, 2015

• See notes, ppt – see ppt on this talk –from Mar 2012

• See notes from previous Willams Review

• END

Endocrinology Emergencies/Disease in

Pregnancy

YEAR 2

AUTOIMMUNE Disease

• Lupus, RA, APLS

PULMONARY

CARDIAC

ID/Fetal Infections/Genetics/

NEUROLOGIC Disease in Pregnancy

Dermatologic Disease in Preg

• See notes, ppt• See notes from previous Willams Review

• END

Dermatologic Disease in Preg

Following slides are notes from 2010-2014

Kidney disease• 24 yo P0000• PKD, Cr 3.5• Prepregnancy evaluation

– Counseling– Management

• Pregnancy counseling– Management

• Inheritance of PKD, AD, variable expressivity/penetrance

Chronic Renal Insufficiency and Pregnancy Outcomes (vs serum creatinine mg/dL)

Outcome Cr<1.5 Cr 1.5-3 Cr >3

PTB 13% 50% 100%

Perinatal death

5% 17% 33%

IUGR 10% 20% 100%

Abortion 11% 21% 25%

Surviving infants

84% 62% 50%

Multifactorial inheritance

• 24 yo G2P1001• Previous child with NTD• Recurrence risk counseling• Folic acid 4mg

– Risk reduction by 70%• Epileptics

– Prepregnancy counseling/eval/management

CF

• Hardy Weinberg eq• - p² +2pq + q²• 1 = p + q• Obligate carrier example• Calc of carrier frequency when given

disease incidence, v/v

Wt gain recommendations

Pulmonary Disease in Pregnancy

Ch 46 – Pulmonary Disease

Lung Volumes• Respiratory rate (# breaths/minute) – no change• Total lung capacity – total amount of volume you can breathe in after

max inspiration– decreased

• Vital capacity – expired vol with maximal exhalation - NC• Residual volume – what is left after maximal exhalation

– volume in lungs after VC• FRC – functional residual capacity – volume remaining after normal

expiration (take normal breath out – how much vol is left in lungs) – Decreased 20%, by 300-500 mL – due to elevation of diaphragm– Changing from sitting to supine at term causes another 25%

decrease in FRC • may increase closure of small airways especially in obese

patients in the supine or lithotomy position• ERV – expiratory reserve volume – (FRC – RV)

– (Vol left after normal breath) – (Vol left after maximal breath)

Other variables

• Airway function – unchanged• Diffusing capacity – unchanged• Oxygen delivery – dependent on Hb

– O2 delivery = CO x CaO2 x 10– CaO2 = (Hgb x 1.34 x SaO2) + (PaO2 x 0.0031)– CaO2 is thus much more dependant on Hgb function than diffusion of

O2 into serum– O2 delivery can be significantly affected by maternal anemia or CO

poisoning– Physiologic anemia of pregnancy is compensated by a 50% increase in

CO (increases in both HR and SV)

Minute Ventilation is Increased• Minute ventilation – RR x TV

– Increases 40% to 100-200cc during early pregnancy and remains constant

• More ventilation at the expense of reserves– Increased AP diameter expansion

• Chest circumference increases 2cm• Diaphragm excursion not impaired,

rather increases– Use up FRC, VC

Respiratory physiology in pregnancy

• Residual volume– volume of air remaining in the lungs after maximal

expiration– decreases 20% due to elevation of diaphragm

• Functional residual capacity (volume of air in lungs at resting expiratory level)– decreases 20% due to elevation of diaphragm– decreases 300-500mL– changing from sitting to supine at term causes

another 25% decrease in FRC • may increase closure of small airways especially in obese

patients in the supine or lithotomy position

Pathophysiologic Implications• Mom is able to hold her breath less

– 1 vs 2 lung example• Decreased FRC

– Closing capacity – amount of volume that has to be behind to keep small airways open - diminished

• Develop hypoxemia quicker than when not pregnant (at greater risk of hypoxemia)

• Pulmonary insults are tolerated less well

ABG Changes in Pregnancy

• *compensatory increase in renal bicarbonate excretion• **decreased in supine position and 3rd trimester• ***increased by 6 in supine position and 3rd trimester

Variable Nonpregnant Pregnant

pH 7.35-7.43 7.4-7.47

pCO2 (mmHg)* 37-40 27-31

pO2 (mmHg)** 103 101-104

P(A-a)O2 (mmHg)*** 14 20

HCO3- (mEq/L) 22-26 18-22

Base deficit (mEq/L) 1 3

Blood Gas Interpretation –Pregnant Women

pO2 pCO2 pH IntepretationNormal Decreased Increased Mild distress,

compensatedDecreased Decreased Increased Moderate distress,

compensatedDecreased Normal (~27-31) Normal Danger – Impaired

VentilationDecreased Increased (>40) Decreased Respiratory

Failure

CXR changes in pregnancy

• apparent cardiomegaly (enlarged transverse diameter)

• enlarged left atrium (lateral views)• increased vascular markings• straightening of left heart border• postpartum pleural effusion (right sided)

Oxygen dissociation

• Right shift causes decreased maternal affinity for O2 (increased levels of 2,3-DPG)

• HbF is unable to react to 2,3-DPG, and so maintains high affinity for O2 despite relative acidemia

• Wedge and CVP Do Not Correlate• SVR is Low Initially, and then Becomes Very

High (along with BP)• Pulmonary Artery Catheter Findings

– Elevated SBP, SVR– Hyperdynamic LV Function– Normal to Increased PCWP– Low CVP– High Wedge with Low CVP May be Due to

Increased Afterload with Volume Depletion

Cardiac Manifestations of Preeclampsia

Pulmonary Edema in Preeclampsia

• Occurs in 3% of Women with Preeclampsia• 70% Occurs Postpartum (Fluid Overload)• Antepartum Pulmonary Edema Associated

with Chronic HTN in 90% Cases• Risk Factors: Older Women, Multigravidas,

Chronic Hypertension• Associated with Fluid Overload, either Colloid

or Crystalloid

Pulmonary Edema in Preeclampsia

• Pathophysiology of Pulmonary Edema– Reduced COP– Alteration of Capillary Membrane

Permeability and Integrity– Elevated Pulmonary Vascular Hydrostatic

Pressures• Extravasation of Fluids in Pulmonary

Interstitium

Pulmonary Edema in Preeclampsia

• Etiology of Pulmonary Edema– Abnormal COP-Wedge Gradient– Capillary Leak– LV Failure

• Non-hydrostatic Forces can Cause Pulmonary Edema

• Fluid Overload is Common, Presenting with Preeclampsia in Pulmonary Edema is Not (If you see it, think LV failure and know that you are in trouble)

Pulmonary Edema in Preeclampsia

• Risk factors – fluid overload, preeclampsia, tocolysis, uncontrolled hypertension

• Diagnosis of Pulmonary Edema– Clinical Diagnosis: Progressive Dyspnea and Chest

Discomfort– Tachypnea, Tachycardia, Bilateral crackles – Confirm with CXR and ABG– Don’t Forget about Pulmonary Embolism

Case

• 34 yo P0, admitted for preeclampsia– IVF pregnancy

• HD #3, developed progressive dyspnea, crackles on physical exam, oxygen requirements– CXR revealed bilateral pleural effusions

• Fluid restriction, diuretics (Lasix 20mgIV), delivery, seizure prophylaxis

CXR of pulmonary edema

Pulmonary Edema in Preeclampsia

• Management– Oxygen, Fluid Restriction, Semi-Fowler– Accurate intake/output– If Fluid Overload, then Lasix, Increasing

Doses as Needed– Consider PA Catheter: Fluid Overload vs.

LV Dysfunction vs. Nonhydrostatic Pulmonary Edema

Indications for PA Catheter in Hypertensive Disease

• Severe preeclampsia with refractory oliguria or pulmonary edema

• Ineffective IV antihypertensive therapy• Intraoperative or intrapartum cardiac

failure

p1169, Creasy

• Management– Intravascular volume depletion (oliguria), low PCWP, high

CO, high SVR, low CVP –• fluids

– Renal Vasoconstriction (High PCWP, Normal CO and SVR, uroconcentration):

• Dopamine – 1-5µg/kg/min; furosemide– LV Dysfunction/Failure with Vasospasm (high PCWP, high

SVR, low CO <5 L/min) : • Needs Afterload Reduction (Sodium nitroprusside 0.25-

0.5µg/kg/min IV infusion) • Volume Restriction• Diuretics (max acute dose of furosemide is 120mg, start with 20-

40mg)– Mechanical Ventilation for Respiratory Failure (If still

Pregnant, Intubate Early rather than Late)

Pulmonary Edema in Preeclampsia – 3 subsets